JPH0794432B2 - Novel phenyl-, pyrrolidin-2-yl-substituted 5-membered heterocyclic compound, method for producing the same, and antipsychotic pharmaceutical composition containing the compound as an active ingredient - Google Patents
Novel phenyl-, pyrrolidin-2-yl-substituted 5-membered heterocyclic compound, method for producing the same, and antipsychotic pharmaceutical composition containing the compound as an active ingredientInfo
- Publication number
- JPH0794432B2 JPH0794432B2 JP62225427A JP22542787A JPH0794432B2 JP H0794432 B2 JPH0794432 B2 JP H0794432B2 JP 62225427 A JP62225427 A JP 62225427A JP 22542787 A JP22542787 A JP 22542787A JP H0794432 B2 JPH0794432 B2 JP H0794432B2
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- pyrrolidin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
【発明の詳細な説明】 本発明は、興味深い薬理学的特性、顕著な抗精神病特性
を有する新規なフエニル,N−アルキルピロリジン−２−
イル置換５員複素環化合物、上記化合物の製造方法、お
よび少なくとも１種の上記化合物、これらの塩または誘
導体を活性物質として含む医薬組成物に関するものであ
る。DETAILED DESCRIPTION OF THE INVENTION The present invention is a novel phenyl, N-alkylpyrrolidine-2-, which has interesting pharmacological properties, remarkable antipsychotic properties.
The present invention relates to an il-substituted 5-membered heterocyclic compound, a method for producing the above compound, and a pharmaceutical composition containing at least one of the above compounds and salts or derivatives thereof as active substances.
次の（１）式 ｛式中のＲは水素原子またはC1〜C3アルキル基、R1はC1
〜C3アルキル基、R2は水素原子、R3はハロゲンまたはC1
〜C3アルキルスルホニル、ｎは０、１または２、Ａは次
の（2a）式 で表される基を示す｝で表される化合物およびその酸付
加塩が、興味深い薬理学特性、顕著な抗精神病特性を有
することを見出した。The following formula (1) {Wherein R is a hydrogen atom or a C 1 -C 3 alkyl group, and R 1 is C 1
~ C 3 alkyl group, R 2 is a hydrogen atom, R 3 is halogen or C 1
To C 3 alkylsulfonyl, n is 0, 1 or 2, and A is the following formula (2a) It has been found that the compound represented by the formula (1) and an acid addition salt thereof have interesting pharmacological properties and remarkable antipsychotic properties.
上記アルキル基は、１〜５個の炭素原子を有し直鎖また
は分枝鎖とすることができる。The alkyl group has 1 to 5 carbon atoms and can be linear or branched.
ハロゲンは塩素または臭素が好ましい。The halogen is preferably chlorine or bromine.
随意に存在するヒドロキシル基はエステル化されていて
もよい。The optionally present hydroxyl groups may be esterified.
これらの特性に基づき好ましい化合物は、（１）式で、
Ｒがメチル、R1がメチルまたはエチル、R2が水素原子、
R3がハロゲン、またはC1〜C3アルキルスルホニル、Ａが
次の（2a）式 で表される基であり、これ以外の記号は前述のものと同
じものを示す場合の化合物である。Preferred compounds based on these characteristics are represented by the formula (1):
R is methyl, R 1 is methyl or ethyl, R 2 is hydrogen atom,
R 3 is halogen, or C 1 -C 3 alkylsulfonyl, A is the following formula (2a) Is a group represented by, and the other symbols are compounds when the same as those described above are shown.
本発明の特に好ましい化合物は、（ａ）２−（２−メト
キシ−５−エチルスルホニルフエニル）−５−（Ｎ−エ
チル−２−ピロリジニル）ピロール、（ｂ）２−（２−
メトキシ−3,5−ジブロモフエニル）−５−（Ｎ−エチ
ル−２−ピロリジニル）ピロールである。Particularly preferred compounds of the present invention are (a) 2- (2-methoxy-5-ethylsulfonylphenyl) -5- (N-ethyl-2-pyrrolidinyl) pyrrole, (b) 2- (2-
Methoxy-3,5-dibromophenyl) -5- (N-ethyl-2-pyrrolidinyl) pyrrole.
本発明の化合物が薬理学的に受け入れられる酸付加塩を
形成し得る適当な酸は、例えば塩酸、硫酸、リン酸、硝
酸および有機酸、例えばクエン酸、フマル酸、マレイン
酸、酒石酸、酢酸、安息香酸、ｐ−トルエンスルホン
酸、メタスルホン酸、ナフタレンスルホン酸等である。Suitable acids with which the compounds of the invention are capable of forming pharmaceutically acceptable acid addition salts are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, Benzoic acid, p-toluenesulfonic acid, metasulfonic acid, naphthalenesulfonic acid and the like.
ラセミ化合物および個々の鏡像体は、本発明に属する。Racemates and individual enantiomers belong to the invention.
本発明の化合物の一部は、興味深い向精神特性を有し、
従って中枢神経系の障害に起因する罹患および疾病の治
療に適当である。これらの化合物は、特有の顕著な抗精
神病活性を有する。本発明の若干の化合物においては、
顕著な他の特性、例えば抗攻撃、抗けいれん、鎮痛、血
圧降下、抗潰瘍または胃運動（gastrokinetic）活性を
呈する。Some of the compounds of the invention have interesting psychotropic properties,
It is therefore suitable for the treatment of morbidity and illness resulting from disorders of the central nervous system. These compounds have unique and prominent antipsychotic activity. In some compounds of the invention,
It exhibits prominent other properties such as anti-aggression, anti-convulsive, analgesic, hypotensive, anti-ulcer or gastrokinetic activity.
２−（２−メトキシ−５−エチルスルホニルフェニル）
−５−（Ｎ−エチル−２−ピロリジニル）ピロールおよ
び２−（２−メトキシ−3,5−ジブロモフェニル）−５
−（Ｎ−エチル−２−ピロリジニル）ピロールに関し
て、抗精神病試験、ドーパミン分解試験および受容体結
合試験を実施した。抗精神病活性は、実験動物（ラッ
ト）の条件付挙動の抑圧をそれ自体知られている方法で
測定する試験方法で測定した。この試験において、ラッ
トが、体重のkg当り100mgまたはそれ以下の経口投与の
後に少なくとも50％の条件付挙動の抑圧を示した場合に
は、化合物が活性であるとみなした。試験した２種の化
合物に関しては、いずれも活性であることが見いだされ
た。2- (2-methoxy-5-ethylsulfonylphenyl)
-5- (N-ethyl-2-pyrrolidinyl) pyrrole and 2- (2-methoxy-3,5-dibromophenyl) -5
Antipsychotic tests, dopamine degradation tests and receptor binding tests were performed on-(N-ethyl-2-pyrrolidinyl) pyrrole. The antipsychotic activity was measured by a test method in which suppression of conditional behavior of experimental animals (rats) was measured by a method known per se. In this test, a compound was considered active if rats showed at least 50% suppression of conditioned behavior following oral administration of 100 mg / kg of body weight or less. Both of the two compounds tested were found to be active.
化合物のドーパミン分解特性（dopaminolyticpropert
y）は、マウスにおいてドーパミンアゴニストアポルモ
ルフィンにより誘発さる挙動（よじのぼり挙動）の抑制
の程度を定める試験方法によって測定した。50mg/kg以
下の投与量を経口投与した後に50％以上の抑制が見出さ
れた場合には、化合物を活性であるとみなした。試験し
た２種の化合物に関しては、いずれも活性であることが
見いだされた。Dopamine degradation properties of compounds
y) was measured by a test method which determines the degree of suppression of the behavior (sinking behavior) induced by the dopamine agonist apormorphine in mice. A compound was considered active if 50% or more inhibition was found after oral administration of a dose of 50 mg / kg or less. Both of the two compounds tested were found to be active.
上述のイン ビボ（in vivo）試験に加えて、イン ビ
トロ（in vitro）受容体結合試験を、脳組織ホモジネ
ートにおいて放射能標識リガンドにより行った。この方
法において、試験した２種の化合物の極めて高い親和性
（100nM以下のKi値で示される）をドーパミン受容体に
対して見出した。これまで臨床において用いられている
大部分のドーパミン分解剤、例えばハロペリドールおよ
び三環式化合物、例えばクロロプロマジンおよびクロザ
ピンと対照的に、上記親和性はナトリウムイオンの存在
に左右される。ユア．ジエ．フアーマコル．（Eur.J.Ph
armacol.）46（1977），第377頁に記載されている如き
実験を行う場合、Naの比率が10〜50の値であることを見
出した。他の神経伝達物質受容体型、例えばコリン作動
性、アドレナリン作動性、セロトニン作動性−受容体
は、極めて低い。In addition to the in vivo studies described above, in vitro receptor binding studies were performed with radiolabeled ligand in brain tissue homogenates. In this way, very high affinities of the two compounds tested (indicated by Ki values below 100 nM) were found for the dopamine receptor. In contrast to most dopamine-degrading agents used clinically to date, such as haloperidol and tricyclics, such as chloropromazine and clozapine, the affinity depends on the presence of sodium ions. Yours. Jie. Fuma Macor. (Eur.J.Ph
armacol.) 46 (1977), p. 377, it was found that the Na ratio has a value of 10-50. Other neurotransmitter receptor types such as cholinergic, adrenergic, serotonergic-receptors are extremely low.
これらの薬理学的データは抗精神病活性が、これまで用
いられているほとんど全ての神経遮断薬の特徴である副
作用の発生をともなわないという意味で化合物の興味深
い臨床的パターンを示す。These pharmacological data demonstrate an interesting clinical pattern of compounds in the sense that their antipsychotic activity is not accompanied by the occurrence of side effects that are characteristic of almost all neuroleptics used to date.
投与量、投与の回数および方法は、個々の場合の病症で
異なり、また障害の性質および激しさに左右される。一
般的に、好ましくは１日１回の投与で５〜500mg、好ま
しくは５〜100mgの１日量をヒトに投与するに用いるこ
とができる。The dose, frequency of administration and method of administration will depend on the disease condition in each case and will depend on the nature and severity of the disorder. Generally, a single daily dose of 5 to 500 mg, preferably 5 to 100 mg, may be used to administer a daily dose to humans.
本発明の活性化合物およびその塩を、従来の補助物質、
例えば固体および液体担体物質を用いながらそれ自体知
られている標準技術により組成物、例えば丸剤、錠剤、
被覆錠剤、カプセル剤、粉剤、注射液等に加工すること
ができる。The active compounds and salts thereof according to the invention are converted into conventional auxiliary substances,
Compositions such as pills, tablets, by standard techniques known per se, for example using solid and liquid carrier materials.
It can be processed into coated tablets, capsules, powders, injection solutions and the like.
これらの化合物およびその酸付加塩および鏡像体を、既
知方法において使用するに適する投与形態を変形するこ
とができる。These compounds and their acid addition salts and enantiomers can be modified in dosage forms suitable for use in the known methods.
本発明の新規な化合物は、類似化合物の合成のために知
られている方法で製造することができる。The novel compounds of this invention can be made by known methods for the synthesis of analogous compounds.
（１）式の化合物の適当な製造方法は、次の（３）式で
表される化合物と（４）式で表されるピロリドン誘導体 （上式中の記号は、前述のものと同じものを示す）との
縮合反応から成る。このカップリングは３工程で行われ
る。第１に、強求電子性試薬を、ルイス酸、例えば三塩
化リン酸、三塩化アルミニウムまたは塩化第二鉄、三フ
ッ化ホウ素、四塩化錫または同等の試薬の群から選ばれ
た活性化試薬の影響下（４）式から作製し、次いで
（３）式の化合物の芳香族５員環Ａにおいて芳香族置換
反応を行う。これらの反応のために適当な溶媒は、塩素
化した炭化水素、例えばジクロロメタン、クロロホル
ム、および1,2−ジクロロエタンである。芳香族溶媒、
例えばベンゼン、トルエンまたはクロロベンゼンを使用
することもできる。Ａの反応性に応じて、温度は−20℃
と用いる溶媒の還流温度との間の温度である。第３工程
においては、アルカリ金属ホウ水素化物またはアルカリ
金属アルミニウム水素化物、例えばホウ水素化ナトリウ
ムの群から選ばれた還元剤を添加する。A suitable method for producing the compound of formula (1) is a compound represented by the following formula (3) and a pyrrolidone derivative represented by formula (4). (The symbols in the above formula represent the same as those described above). This coupling is done in three steps. First, a strong electrophilic reagent is used as the activating reagent selected from the group of Lewis acids such as phosphoric acid trichloride, aluminum trichloride or ferric chloride, boron trifluoride, tin tetrachloride or equivalent reagents. Under the influence, it is prepared from the formula (4), and then an aromatic substitution reaction is carried out in the aromatic 5-membered ring A of the compound of the formula (3). Suitable solvents for these reactions are chlorinated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane. Aromatic solvent,
It is also possible to use, for example, benzene, toluene or chlorobenzene. The temperature is -20 ℃ depending on the reactivity of A.
And the reflux temperature of the solvent used. In the third step, a reducing agent selected from the group of alkali metal borohydrides or alkali metal aluminum hydrides, such as sodium borohydride, is added.
（３）式の出発化合物は、それ自体知られている環化反
応により得ることができる。Ａが２位の置換されたピロ
ール環またはフラン環である場合には、モナツシエフテ
フュア ケミー（Monatshefte fr Chemie）108（19
77），第285頁に記載されている如く上記環化は対応す
る1,4−ジカルボニル化合物と行われる。The starting compound of formula (3) can be obtained by a cyclization reaction known per se. When A is a substituted pyrrole ring or furan ring at the 2-position, Monatshefte fr Chemie 108 (19
77), page 285, the cyclization is carried out with the corresponding 1,4-dicarbonyl compound.
Ａが１位の置換されたピラゾール環である場合には、英
国特許第797,144号明細書、ケミカルアブストラクト（C
hem.Abstr.）53，（1959）,4983iに記載されている如く
対応するアリールヒドラジンをマロン酸ジアルデヒドテ
トラメチルアセタールで処理する。When A is a substituted pyrazole ring at the 1-position, British Patent No. 797,144, Chemical Abstracts (C
Chem. Abstr.) 53 , (1959), 4983i and the corresponding arylhydrazine is treated with malonic dialdehyde tetramethylacetal.
（１）式のR2またはR3基がヒドロキシル基である場合、
かかる化合物は、最終反応工程として（１）式の対応す
る化合物から保護基（protective gronp）を離脱するこ
とによって得ることができる。ＲおよびR1〜R3の意味の
範囲内の他の化学転化、例えば還元反応を、最終工程と
して用いることもできる。When the R 2 or R 3 group of formula (1) is a hydroxyl group,
Such a compound can be obtained by removing the protective group from the corresponding compound of the formula (1) in the final reaction step. Other chemical conversions within the meaning of R and R 1 to R 3 , such as reduction reactions, can also be used as final step.
以下、本発明を実施例による更に詳細に説明する。Hereinafter, the present invention will be described in more detail with reference to Examples.
実施例１ ２−（２−メトキシ−５−エチルスルホニルフエニル）
−５−（Ｎ−エチル−２−ピロリジニル）ピロール 反応は、乾燥窒素雰囲気下で行った。0.27ml（3mMol）
の三塩化リンを340mg〔３ミリモル（mMOl）〕のＮ−エ
チルピロリドン−２に10分間で滴下した。室温で15分間
かき混ぜた後、5mlの1,2−ジクロロエタンを添加した。
溶液を０℃の温度に冷却し、しかる後3mMol（795mg）の
２−（２−メトキシ−５−エチルスルホニルフエニル）
ピロールを9mlの1,2−ジクロロエタンに溶解した溶液を
約20分間で滴下した。反応混合物を室温で16時間かき混
ぜ、次いで０℃の温度に冷却し、次いで1.0gのホウ水素
化ナトリウムを添加した。室温で２時間かき混ぜた後、
混合物を再び０℃の温度に冷却し、次いでまず5mlのメ
タノール、次いで30mlの水を緩徐に添加した。室温で１
時間かき混ぜた後、反応混合物をジクロロメタン（３×
15ml）で抽出した、有機層を硫酸マグネシウム上で乾燥
し、次いで減圧濃縮した。1.2gの黄色油状物を得た。３
％のメタノールを含有するジクロロメタンおよび15％の
メタノールを含有するジクロロメタン夫々を用いてシリ
カゲルカラムでクロマトグラフィーして、２−（２−メ
トキシ−５−エチルスルホニルフエニル）−５−（Ｎ−
エチル−２−ピロリジニル）ピロールを、45℃の温度の
融点を有する淡茶色粉末にて600mgの収量（収率55％）
で得た。Example 1 2- (2-Methoxy-5-ethylsulfonylphenyl)
-5- (N-Ethyl-2-pyrrolidinyl) pyrrole The reaction was performed under a dry nitrogen atmosphere. 0.27 ml (3 mMol)
Phosphorus trichloride was added dropwise to 340 mg [3 mmol (mMOl)] of N-ethylpyrrolidone-2 in 10 minutes. After stirring for 15 minutes at room temperature, 5 ml of 1,2-dichloroethane was added.
The solution was cooled to a temperature of 0 ° C. and then 3 mMol (795 mg) 2- (2-methoxy-5-ethylsulfonylphenyl).
A solution of pyrrole in 9 ml of 1,2-dichloroethane was added dropwise over about 20 minutes. The reaction mixture was stirred at room temperature for 16 hours, then cooled to a temperature of 0 ° C. and then 1.0 g of sodium borohydride was added. After stirring for 2 hours at room temperature,
The mixture was cooled again to a temperature of 0 ° C., then 5 ml of methanol and then 30 ml of water were added slowly. 1 at room temperature
After stirring for an hour, the reaction mixture was diluted with dichloromethane (3x
15 ml), the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. 1.2 g of a yellow oil was obtained. Three
Chromatography on a silica gel column with dichloromethane containing 15% methanol and dichloromethane containing 15% methanol gave 2- (2-methoxy-5-ethylsulfonylphenyl) -5- (N-
The yield of ethyl-2-pyrrolidinyl) pyrrole was 600 mg as a light brown powder having a melting point of 45 ° C. (yield 55%).
Got with.
実施例２ ２−（２−メトキシ−3,5−ジブロモフエニル）−５−
（Ｎ−エチル−２−ピロリジニル）−ピロール 上記化合物を、２−（２−メトキシ−3,5−ジブロフエ
ニル）ピロールから出発して実施例１に記載の方法と同
様の方法で得た。カラムクロクトグラフィーの後の純粋
生成物は、油状物であった。Example 2 2- (2-Methoxy-3,5-dibromophenyl) -5-
(N-Ethyl-2-pyrrolidinyl) -pyrrole The above compound was obtained in a similar manner to that described in Example 1 starting from 2- (2-methoxy-3,5-dibrophenyl) pyrrole. The pure product after column chromatography was an oil.
実施例１および２の化合物のプロトン−NMRデータは、
予期された構造と十分に一致した。Proton-NMR data for the compounds of Examples 1 and 2 are:
It is in good agreement with the expected structure.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 ヨハネス・アントニウス・マリア・ファ ン・デル・ヘイデン オランダ国ウエースプ セー イエー フ アン ホウテンラーン36 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Johannes Antonius Maria van der Haden The Netherlands Wesp See Yehuan Houtenlarn 36
Claims (5)
〜C3アルキル基、R2は水素原子、R3はハロゲンまたはC1
〜C3アルキルスルホニル、ｎは０、１または２、Ａは次
の（2a）式 で表される基を示す｝で表されることを特徴とするフェ
ニル、ピロリジン−２−イル置換５員複素環化合物およ
びその酸付加塩。1. The following formula (1) {Wherein R is a hydrogen atom or a C 1 -C 3 alkyl group, and R 1 is C 1
~ C 3 alkyl group, R 2 is a hydrogen atom, R 3 is halogen or C 1
To C 3 alkylsulfonyl, n is 0, 1 or 2, and A is the following formula (2a) And a phenyl-, pyrrolidin-2-yl-substituted 5-membered heterocyclic compound and an acid addition salt thereof.
が水素原子、R3がハロゲンまたはC1〜C3アルキルスルホ
ニル、Ａが（2a）式で表される基であり、ｎは特許請求
の範囲第１項記載のものと同じものである特許請求の範
囲第１項記載の化合物およびその酸付加塩。2. R is methyl, R 1 is methyl or ethyl, R 2
Is a hydrogen atom, R 3 is halogen or C 1 -C 3 alkylsulfonyl, A is a group represented by the formula (2a), and n is the same as in claim 1. And a acid addition salt thereof.
ルフェニル）−５−（Ｎ−エチル−２−ピロリジニル）
ピロールまたは２−（２−メトキシ−3,5−ジブロモフ
ェニル）−５−（Ｎ−エチル−２−ピロリジニル）ピロ
ールである特許請求の範囲第１項記載の化合物およびそ
の酸付加塩。3. 2- (2-Methoxy-5-ethylsulfonylphenyl) -5- (N-ethyl-2-pyrrolidinyl)
The compound according to claim 1, which is pyrrole or 2- (2-methoxy-3,5-dibromophenyl) -5- (N-ethyl-2-pyrrolidinyl) pyrrole, and an acid addition salt thereof.
〜C3アルキル基、R2は水素原子、R3はハロゲンまたはC1
〜C3アルキルスルホニル、ｎは０、１または２、Ａは
（2a）式で表される基を示す｝で表される化合物を製造
するに当たり、次の（３）式 （式中のR1、R2、R3およびＡは上述のものと同じものを
示す）で表される化合物を、次の（４）式 （式中のＲは上述のものと同じものを示す）で表される
化合物で転化することを特徴とするフェニル、ピロリジ
ン−２−イル置換５員複素環化合物の製造方法。4. The following formula (1) {Wherein R is a hydrogen atom or a C 1 -C 3 alkyl group, R 1 is C 1
~ C 3 alkyl group, R 2 is a hydrogen atom, R 3 is halogen or C 1
To C 3 alkylsulfonyl, n is 0, 1 or 2, and A is a group represented by the formula (2a)}, and a compound represented by the following formula (3) (Wherein R 1 , R 2 , R 3 and A are the same as those described above), a compound represented by the following formula (4) A method for producing a phenyl-, pyrrolidin-2-yl-substituted 5-membered heterocyclic compound, which comprises converting with a compound represented by the formula (wherein R represents the same as described above).
〜C3アルキル基、R2は水素原子、R3はハロゲンまたはC1
〜C3アルキルスルホニル、ｎは０、１または２、Ａは
（2a）式で表される基を示す｝で表される少なくとも１
種のフェニル、ピロリジン−２−イル置換５員複素環化
合物を活性物質として含有することを特徴とする抗精神
病医薬組成物。5. The following formula (1) {Wherein R is a hydrogen atom or a C 1 -C 3 alkyl group, and R 1 is C 1
~ C 3 alkyl group, R 2 is a hydrogen atom, R 3 is halogen or C 1
To C 3 alkylsulfonyl, n is 0, 1 or 2, and A is a group represented by the formula (2a)}
An antipsychotic pharmaceutical composition comprising a phenyl, pyrrolidin-2-yl-substituted 5-membered heterocyclic compound as an active substance.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8602305 | 1986-09-12 | ||
| NL8602305 | 1986-09-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6377856A JPS6377856A (en) | 1988-04-08 |
| JPH0794432B2 true JPH0794432B2 (en) | 1995-10-11 |
Family
ID=19848538
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62225427A Expired - Lifetime JPH0794432B2 (en) | 1986-09-12 | 1987-09-10 | Novel phenyl-, pyrrolidin-2-yl-substituted 5-membered heterocyclic compound, method for producing the same, and antipsychotic pharmaceutical composition containing the compound as an active ingredient |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4791132A (en) |
| EP (1) | EP0259930B1 (en) |
| JP (1) | JPH0794432B2 (en) |
| AT (1) | ATE72435T1 (en) |
| AU (1) | AU609415B2 (en) |
| DE (1) | DE3776611D1 (en) |
| DK (1) | DK166275C (en) |
| ES (1) | ES2033297T3 (en) |
| GR (1) | GR3004436T3 (en) |
| IE (1) | IE60294B1 (en) |
| IL (1) | IL83841A (en) |
| NZ (1) | NZ221731A (en) |
| PH (1) | PH23898A (en) |
| ZA (1) | ZA876749B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992441A (en) * | 1987-10-14 | 1991-02-12 | Mcneilab, Inc. | 1-[[5-[[4-substituted-1-piperazinyl]methyl]-pyrrol-2-yl or furan-2-yl]methyl-2-piperidinones useful in treating schizophrenia |
| EP0654023B1 (en) * | 1992-08-06 | 1998-09-16 | Smithkline Beecham Plc | 5-(2-oxyphenyl)-pyrrole derivatives as dopamine d3 receptor antagonists |
| GB9307400D0 (en) * | 1993-04-08 | 1993-06-02 | Smithkline Beecham Plc | Compounds |
| GB9309573D0 (en) * | 1993-05-10 | 1993-06-23 | Merck Sharp & Dohme | Therapeutic agents |
| JPH08511789A (en) * | 1993-06-25 | 1996-12-10 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Phenylpyrrole derivatives and their use as dopamine D3 antagonists |
| GB9315800D0 (en) * | 1993-07-30 | 1993-09-15 | Smithkline Beecham Plc | Compounds |
| GB9315801D0 (en) * | 1993-07-30 | 1993-09-15 | Smithkline Beecham Plc | Compounds |
| GB9320855D0 (en) * | 1993-10-09 | 1993-12-01 | Smithkline Beecham Plc | Compounds |
| GB9402197D0 (en) * | 1994-02-04 | 1994-03-30 | Smithkline Beecham Plc | Compounds |
| GB9403199D0 (en) * | 1994-02-19 | 1994-04-13 | Smithkline Beecham Plc | Compounds |
| GB9512129D0 (en) * | 1995-06-15 | 1995-08-16 | Smithkline Beecham Plc | Compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4219560A (en) * | 1978-04-17 | 1980-08-26 | Sandoz, Inc. | Piperidine and pyrrolidine alcohols |
| DE2835439A1 (en) * | 1978-08-12 | 1980-02-28 | Basf Ag | 2- (O-HYDROXYPHENYL) -PYRROL |
| US4321385A (en) * | 1980-02-04 | 1982-03-23 | Hoechst Roussel Pharmaceuticals Inc. | [(Aryl-1-pyrryl) methyl]-piperidinols and pyrrolidinols |
| US4539332A (en) * | 1983-11-14 | 1985-09-03 | Merck & Co., Inc. | 2,5-Diaryl tetrahydrofurans and analogs thereof as PAF-antagonists |
-
1987
- 1987-09-08 PH PH35780A patent/PH23898A/en unknown
- 1987-09-09 IE IE240987A patent/IE60294B1/en not_active IP Right Cessation
- 1987-09-09 DE DE8787201706T patent/DE3776611D1/en not_active Expired - Fee Related
- 1987-09-09 DK DK470687A patent/DK166275C/en active
- 1987-09-09 IL IL83841A patent/IL83841A/en not_active IP Right Cessation
- 1987-09-09 ES ES198787201706T patent/ES2033297T3/en not_active Expired - Lifetime
- 1987-09-09 EP EP87201706A patent/EP0259930B1/en not_active Expired - Lifetime
- 1987-09-09 US US07/094,746 patent/US4791132A/en not_active Expired - Fee Related
- 1987-09-09 NZ NZ221731A patent/NZ221731A/en unknown
- 1987-09-09 AT AT87201706T patent/ATE72435T1/en not_active IP Right Cessation
- 1987-09-09 AU AU78191/87A patent/AU609415B2/en not_active Ceased
- 1987-09-09 ZA ZA876749A patent/ZA876749B/en unknown
- 1987-09-10 JP JP62225427A patent/JPH0794432B2/en not_active Expired - Lifetime
-
1992
- 1992-04-22 GR GR920400808T patent/GR3004436T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ221731A (en) | 1990-07-26 |
| DK166275B (en) | 1993-03-29 |
| US4791132A (en) | 1988-12-13 |
| IE60294B1 (en) | 1994-06-29 |
| DK166275C (en) | 1993-08-23 |
| IE872409L (en) | 1988-03-12 |
| EP0259930A1 (en) | 1988-03-16 |
| ES2033297T3 (en) | 1993-03-16 |
| IL83841A0 (en) | 1988-02-29 |
| ATE72435T1 (en) | 1992-02-15 |
| GR3004436T3 (en) | 1993-03-31 |
| DE3776611D1 (en) | 1992-03-19 |
| IL83841A (en) | 1991-11-21 |
| JPS6377856A (en) | 1988-04-08 |
| AU7819187A (en) | 1988-03-17 |
| AU609415B2 (en) | 1991-05-02 |
| DK470687D0 (en) | 1987-09-09 |
| DK470687A (en) | 1988-03-13 |
| EP0259930B1 (en) | 1992-02-05 |
| PH23898A (en) | 1989-12-18 |
| ZA876749B (en) | 1988-03-14 |
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